Adenosine is known to be an endogenous modulator of a number of physiological functions. At the cardiovascular system level, adenosine is a strong vasodilator and a cardiac depressor. On the central nervous system, adenosine induces sedative, anxiolytic and antiepileptic effects. On the respiratory system, adenosine induces bronchoconstriction. At the kidney level, it exerts a biphasic action, inducing vasoconstriction at low concentrations and vasodilation at high doses. Adenosine acts as a lipolysis inhibitor on fat cells and as an antiaggregant on platelets.
Adenosine action is mediated by the interaction with different membrane specific receptors which belong to the family of receptors coupled with G proteins. Biochemical and pharmacological studies, together with advances in molecular biology, have allowed the identification of at least four subtypes of adenosine receptors: A1, A2A, A2b and A3. A1 and A3 are high-affinity, inhibiting the activity of the enzyme adenylate cyclase, and A2A and A2b are low-affinity, stimulating the activity of the same enzyme.
Analogs of adenosine able to interact as antagonists with the A1, A2A, A2b and A3 receptors have also been identified. Selective antagonists for the A2A receptor are of pharmacological interest because of their reduced level of side affects. In the central nervous system, A2A antagonists can have antidepressant properties and stimulate cognitive functions. Moreover, data has shown that A2A receptors are present in high density in the basal ganglia, known to be important in the control of movement. Hence, A2A antagonists can improve motor impairment due to neurodegenerative diseases, for example, Parkinson's disease, senile dementia as in Alzheimer's disease, and psychoses of organic origin.
Some xanthine-related compounds have been found to be A1 receptor selective antagonists, and xanthine and non-xanthine compounds have been found to have high A2A affinity with varying degrees of A2A vs. A1 selectivity. Triazolo-pyrimidine adenosine A2A receptor antagonists with different substitution at the 7-position have been disclosed previously, for example in WO 95/01356; U.S. Pat. No. 5,565,460; WO 97/05138; and WO 98/52568.
Parkinson's disease is characterized by progressive degeneration of the nigrostriatal dopaminergic pathway. The subsequent reduction in striatal dopamine levels is responsible for motor symptoms associated with Parkinson's disease, e.g., the loss of fine motor control or motor impairment manifested in those suffering from the disease. Current methodologies for alleviating motor symptoms associated with Parkinson's disease seek to replace dopamine either within the presynaptic terminal, for example, by administration of L-Dopa, directly through stimulation of the postsynaptic D2 receptors, or by inhibiting metabolism, for example, by administration of monoamine oxidase type B (MAO-B) or catechol-O-methyltransferase (COMT). Long term use of such therapies is often associated with adverse events. For example, long term therapy with L-Dopa (currently the standard of care) is often associated with adverse events (e.g. motor complications), for example, “wearing-off”, “random on-off” oscillations, or dyskinesia. These motor complications arising from therapy administered to manage Parkinson's disease often become progressively more severe with continued treatment.
As mentioned above, A2A receptors are present in high density in the basal ganglia and are known to be important in the control of fine motor movement. Highly selective A2A antagonists have demonstrated their efficacy in reducing motor symptoms associated with neurodegenerative diseases. Accordingly, compounds which are A2A receptor antagonists are believed to be useful in alleviating motor symptoms associated with Parkinson's disease. For example, U.S. Pat. No. 6,630,475 to Neustadt et al. (the '475 patent) describes the preparation of the compound of Formula PI:

In the '475 patent example Schemes 1 to 5, along with preparative Schemes 1 to 4, show general methods of preparing compounds of Formula IA. The '475 patent describes also that the compound of Formula I can be prepared as a pharmaceutically acceptable salt which may be useful for treating Parkinson's disease.
Another example, U.S. Pat. No. 8,389,532 to Boyle et al. (the '532 patent) describes the preparation of the compound of Formula IB:

The compounds of Formulae IA and IB are both poorly soluble in a basic environment, such as the intestine, and in particular, when the compound of Formula I is co-administered with a proton-pump inhibitor a sharp drop in bioavailability has been observed.
The use of A2A receptor antagonists, for example, those of Formulae IA and IB requires a dosage form providing an ability to administer the compound to a patient in need thereof and desirably, the dosage form will afford dosage periodicity that minimizes the number of times it must be administered in a given period. Such dosage forms are believed to provide improved compliance and effect improved therapeutic outcome by minimizing therapeutic compound serum peak and trough levels and providing desired trough conc's of the drug at specific times (e.g C12 or C24 trough conc's) and/or exposure levels of the drug that is comparable to the more frequently administered immediate release dosage forms which are believed to have value in the treatment of central nervous system disorders, in particular treating or managing the progression of such diseases, for example, but not limited to, Parkinson's disease.
Solid dispersions, and, particularly, solid solutions, have been employed to promote the oral absorption of poorly water soluble active pharmaceutical ingredients (APIs), see, for example, Ford, Pharm Acta Helv, 1986, 61:69-88. Solid dispersions and solid solutions are compositions in which API is dispersed into or dissolved in a solid matrix, generally a polymer matrix. Solid solutions and solid dispersions (in which the active pharmaceutical ingredient forms a homogeneous or nearly homogeneous glass in the excipient matrix) are of particular interest in the oral delivery of poorly water soluble compounds. It is believed that these materials improve the absorption of orally administered API by improving: (i) the wetting properties of the API; (ii) causing at the point of absorption transient supersaturation of the API with respect to a lower energy (e.g. crystalline) phase API; or (iii) both effects. In general, solid solutions are believed to enable drug absorption by enhancing the dissolution rate and/or the extent to which the drug is dissolved from the matrix.
One example of a Class II drug which has been formulated as a solid solution is posaconazole, as described in International Patent Application, publication no. WO2009/129300, published Oct. 22, 2009. Such compositions of posaconazole were prepared by forming an extrudate of posaconazole in hydroxypropylmethylcellulose acetate-succinate-derivatized polymer (HPMC-AS), which solid dispersion was subsequently blended with microcrystalline cellulose, additional HPMC-AS, hydroxypropylcellulose, and magnesium sterate. This admixture was tableted to provide an orally bioavailable posaconazole formulation with desirable PK and bioavailability.
Another example of polymers employed in providing a solid solution of polymer and API is reported by Goertz et al. in U.S. Pat. No. 4,801,460 describes solid dispersions comprising a poorly soluble drug (exemplified by theophylline) and cross-linked polyvinylpyrrolidone/vinyl acetate copolymer (PVP copolymer). The '460 patent reports drug release times of up to 8 hours in tests employing such polymer matrix solid solutions.
In another example, Fry et al. describe formulations of HER-2 inhibitors dispersed in a wide variety of polymer matricies, including many different derivatives of cellulosic polymers (including graft copolymers incorporating cellulosic moieties), polyvinyl alcohol polymers and polyvinylpyrrolidine polymers. See published international application publication no. WO2013/056108, published Apr. 18, 2013. Such compositions are said to reduce interpatient PK variability.
Despite their growing use, the design of solid solution formulations to effectively promote oral drug absorption remains largely a matter of trial and error. Successful formulation of lipophilic compounds as solid dispersions to promote oral absorption may benefit from a strong interaction between API and polymer. This has led to interest in partially water soluble polymers with amphiphilic properties like hydroxypropyl methylcellulose acetate succinate (HPMCAS), especially when the process used to create the solid dispersion is spray drying. See Friesen et al., Mol. Pharm., 2008, 5:1003-1019. While this approach was successful for many drug candidates, it was suggested that compounds with high melting points (or high ratios of melting point to glass transition temperature) and/or particularly lipophilic compounds (e.g., those with high log P values) are especially problematic to successfully formulate as solid solutions. Friesen et al. suggests that successful formulations of compounds having high melting point properties will likely be limited to relatively dilute concentrations of API in the solid dispersion.
In another report, controlled-release indomethacin-containing acrylic-based polymer dispersion formulations prepared by hot-melt extrusion (HME) using Eudragit® RD-100 in combination with one or more of Eudragit® L-100, Eudragit® S-100 or Eudragit® RE-100 to modify release rates have been prepared (Drug Development and Industrial Pharmacy, 2006 (32) pp 569 to 583), however this report indicates that formulations containing 51 wt. % Eudragit® RD100 and 10 wt. % Eudragit® S-100 exhibit release that in acid environments are unacceptable low and in neutral environments approach immediate release profiles (see FIG. 9 C therein).
Some studies have demonstrated dosage forms based upon acrylate polymers which undergo slow degradation in the environment in which the active is to be released, for example, for example, the previous study cited using Eudragit® RD 100, however, no controlled release formulations have been demonstrated which provide the desired trough concentrations and exposure levels necessary to provide a once-daily (QD) dosage form for compounds of Formula I or Formula II.